Synergistic intraocular pressure lowering combinations

ABSTRACT

Herein is described an ocular composition comprising an ocular decongestant such as phenylephrine and certain labdane derivatives which are intraocular pressure lowering agents. The composition not only markedly reduces the ocular reddening otherwise produced by such labdane compounds, but also unexpectedly prolongs and frequently potentiates their intraocular pressure lowering effect. Both of these effects are very beneficial to the use of such labdanes for the treatment of glaucoma. 
     Also described herein is an ocular composition comprising para-aminoclonidine (an α 2  -adrenoreceptor agonist) and certain labdane derivatives mentioned above. The composition reduces the ocular reddening and lacrimation, and also potentiates the intraocular pressure lowering effect.

CROSS-REFERENCE TO RELATED APPLICATION

This is a continuation of application Ser. No. 08/709,705, filed Sep. 9, 1996; now abandoned, which is a continuation of application Ser. No. 07/479,707 filed Feb. 15, 1990, now abandoned; which is a continuation-in-part of application Ser. No. 07/105,850, filed Oct. 8, 1987, now U.S. Pat. No. 4,902,696, which is herein incorporated by reference.

The present invention is directed to an ocular composition comprising an ocular decongestant such as phenylephrine and certain derivatives of labdane depicted by Formula I which are intraocular pressure lowering agents. Such combinations not only markedly reduce the ocular reddening (hyperemia) otherwise produced by such labdanes but also unexpectedly prolong and frequently potentiate their intraocular pressure lowering effect. This invention is also directed to a method of lowering intraocular pressure in mammals which comprises administration of a composition comprising an ocular decongestant and a labdane compound of Formula I.

The present invention is also directed to an ocular composition comprising para-aminoclonidine (known to be an α₂ -adrenoreceptor agonist) and certain labdane derivatives mentioned above as well as to a method of lowering intraocular pressure in mammals which comprises administrating such an ocular composition.

The labdane derivatives used in this invention have Formula I below, ##STR1## wherein ##STR2## where R₂ is hydrogen, loweralkyl, ##STR3## where m is 1, 2 or 3, R₁ is loweralkyl, p is 0, 1, 2 or 3, R₁₄, R₁₅ and R₁₆ are each independently hydrogen or loweralkyl;

R₃ is hydrogen, loweralkyl, --(CH₂)_(q) OR₁₇ or --CH₂ CHOHCH₂ OH, where q is 0, 2 or 3 and R₁₇ is hydrogen or loweralkyl; R₄ is hydrogen, loweralkyl or --(CH₂)_(r) OH where r is 2 or 3, or alternatively --NR₃ R₄ as a whole is ##STR4## where n is 0, 1 or 2 and ##STR5## R₁₈ being hydrogen, loweralkyl, loweralkoxy or loweralkylcarbonyloxy, and R₁₉ being loweralkyl;

R₅ is hydrogen, loweralkyl, benzyl or hydroxymethyl; and

R₁₀, R₁₁ and R₁₂ are each independently loweralkyl;

(b) R₉ is hydrogen, or alternatively to the above, R₁ and R₉ taken together form ##STR6## where R₂₀ and R₂₁ are each independently loweralkyl, or alternatively --NR₂₀ R₂₁ as a whole is ##STR7## where n' has the same definition as n but is independent thereof and X' has the same definition as X but is independent thereof; and

(c) R₆ and R₇ are each independently ##STR8## or taken together form ##STR9## where R'₂, R'₃, R'₄ and R'₅ have the same definitions as R₂, R₃, R₄ and R₅, respectively, but are independent thereof, respectively.

The compounds of formula I and methods of synthesizing them are disclosed for instance in Bajwa et al., U.S. Pat. No. 4,134,986; U.S. patent application Ser. No. 804,405, filed Jul. 24, 1986 (see also U.S. Pat. No. 4,639,446) which is a continuation-in-part of Ser. No. 681,779 filed Dec. 4, 1984; U.S. patent application Ser. No. 848,053 filed Apr. 4, 1986 (see also U.S. Pat. No. 4,639,443) which is a continuation-in-part of Ser. No. 707,283 filed Mar. 1, 1985; and U.S. patent application Ser. No. 947,070 filed Apr. 4, 1986.

It is known that the labdane compounds of formula I have the effect of reducing intraocular pressure in mammals. However, when administered topically, they also cause redness (hyperemia) in the eyes, which is very undesirable from the standpoint of practical utility of these compounds.

It has now been found that when an ocular decongestant such as phenylephrine, is used in combination with a labdane compound of formula I, the composition not only markedly reduces the ocular reddening which is otherwise produced by such labdane compounds, but also unexpectedly prolongs and frequently potentiates their intraocular pressure lowering effect. Both of these effects are very beneficial to the use of such labdanes for the treatment of glaucoma.

In this invention, an ocular decongestant (an agent which reduces or suppresses redness in the eye, for instance, phenylephrine) and the labdane compound of formula I are combined in a single dosage form using a suitable vehicle. Typically the concentration of phenylephrine in the ocular composition of this invention is between 0.01% and 3.0% by weight, preferably between 0.12% and 0.20%. Typically the concentration of the labdane compound in the ocular composition is between 0.1% and 1.0% by weight. Any suitable vehicle for ocular compositions known in the art can be used in this invention. An example of such vehicle is shown below.

    ______________________________________                                         An Example of Vehicle                                                          Component            Concentration                                             ______________________________________                                         Benzalkonium chloride                                                                               0.01%                                                     Edetate disodium     0.01%                                                     Sodium phosphate monobasic (pH 7.4)                                                                 0.175%                                                    Sodium phosphate dibasic (pH 7.4)                                                                   0.81%                                                     Sodium chloride      0.41%                                                     HPMC (methocel E-15)  2.0%                                                     Polysorbate 20        5.0%                                                     Triple distilled water                                                                              q.s. 100%                                                 ______________________________________                                    

The ocular composition of this invention is applied topically to the eye using a conventional means such as an eye dropper. A typical amount of administration is three times 20 microliters at two to three minute intervals.

In ascertaining the effect of this invention, samples of ocular composition comprising suitable amounts of phenylephrine and a labdane compound of formula I were prepared and a test was conducted in the following manner.

Method

Each New Zealand white rabbit (NZW, 2.0 to 2.5 kg) was acclimated to the laboratory environment and the procedure at least one day prior to experimentation. Acclimation consisted of handling the animal as well as taking IOP (intraocular pressure) measurements in the absence of drug.

IOP measurements consisted of topically administering one drop (approximately 50 microliters) of a short-acting local anesthetic (Ophthaine 0.5%) directly on the eyes of an unrestrained rabbit. Approximately 40-45 seconds following local anesthetic administration, an IOP reading for each eye was taken for 10 seconds and recorded in mmHg. IOP was determined by applanation pneumotonometry using an Alcon pneumatonograph uncalibrated for the rabbit eye.

On the day of the experiment, two baseline IOP measurement, were determined and designated as P₁ and P₂, respectively. The P₁ measurement was recorded 30 minutes prior to drug administration while the P₂ measurement occurred just prior to drug or placebo administration. The P₂ measurement was the designated IOP at zero (0) time and was used as the baseline control value for the determination of percent reduction in outflow pressure. Thus, a baseline value was determined for each rabbit studied.

Immediately following the P₂ measurement, the appropriate concentration of drug or vehicle was administered topically to the right eye of the rabbits. This was done by placing three successive 20 microliter additions directly onto the eye at two- to three-minute intervals. In addition, during drug application, the lower eyelid was held so that excess fluid was collected in the exposed conjunctival sac. Simultaneously, the left eye received vehicle with the same regimen as the drug-treated right eye. The vehicle (control) treatment was to monitor potential contralateral ocular effects. Following drug or vehicle treatment, IOP measurements were taken as described above characteristically at the following time periods: 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0 and 6.0 hours. Additional monitoring was performed as dictated by the response of the drug.

The IOP of each rabbit eye for each time period was initially recorded in mmHg. However, to account for initial IOP differences among rabbits, the changes in mmHg were normalized by converting to percent reduction in outflow pressure (ROP). The ROP was calculated according to an equation proposed by Mishima ("Clinical Pharmacokinetics of the Eye", Invest. Ophthalmol. Vis. Sci. 21, 504-541 (1981)): ##EQU1## where Po is the IOP reading in mmHg at zero time, Pe is the experimental IOP reading in mmHg at the appropriate time following drug or vehicle administration and Ep is episcleral venous pressure taken as a constant of 10 mmHg. The percent ROP for each rabbit at each time period studied was recorded and grouped to determine a mean percent ROP for each time period as well as the duration of activity.

Phenylephrine hydrochloride (0.12% or 1%) and test drug were combined directly in the aforementioned vehicle.

The experimental IOP measurements were compared statistically to the pretreatment IOP measurements by means of the paired Students t-test, P<0.05.

Results

One effect produced by direct adenylate cyclase stimulators such as labdane compounds of formula I after topical ocular administration is vasodilatation resulting in local hyperemia. To circumvent this effect, such compounds are combined with a low concentration of phenylephrine. Table 1 lists the effects of the drug combinations on IOP in the noraml NZW rabbit.

Upon gross observation and subjective grading, phenylephrine greatly attenuated the hyperemia produced by compounds I. Phenylephrine at a low concentration (0.12%) enhances both the IOP lowering effect and duration of activity of compounds I. This effect is enhanced by increasing the concentration of phenylephrine to 1%.

                                      TABLE 1                                      __________________________________________________________________________                      Maximal %                                                                              Time of                                                                             Times post-                                                  N    reduction outflow                                                                      maximal                                                                             administration                                   Drug Phenylephrine                                                                         (no. of                                                                             pressure (ROP)                                                                         % ROP                                                                               of significant                                   conc.                                                                               concentration                                                                         subjects)                                                                           (mean ± S.E.M.)                                                                     (hour)                                                                              ROP (hour)                                       __________________________________________________________________________     A, 0.1%                                                                               0%   49   40.2 ± 3.3.sup.a                                                                    1.5  0.5-5                                            B, 1%                                                                                 0%   42   34.2 ± 3.4.sup.a                                                                    1    0.5-3                                            none 0.12%  15   11.2 ± 1.5.sup.                                                                     3    NSR.sup.b                                        A, 0.1%                                                                             0.12%  15   49.7 ± 4.5.sup.a                                                                    1    0.5-7                                            A, 0.1%                                                                               1%   5    73.8 ± 4.1.sup.a                                                                    0.5  0.5-7                                            B, 1%                                                                               0.12%  5     30.6 ± 10.4.sup.a                                                                  0.5    0-1                                            C, 0.1%                                                                               0%   5    66.2 ± 8.6.sup.a                                                                    1      1-3                                            C, 0.25%                                                                              0%   10   53.1 ± 5.8.sup.a                                                                    1      1-4                                            C, 0.25%                                                                            0.12%  5     65.0 ± 13.9.sup.a                                                                  1    0.5-5                                            D, 0.1%                                                                              0.0%  15    35.6 ± 10.3.sup.a                                                                  0.5  0.5-2                                            D, 0.1%                                                                             0.12%  5     31.4 ± 11.0.sup.a                                                                  6      4-8                                            E, 0.1                                                                                0%   15   52.5 ± 9.5.sup.a                                                                    1    0.5-4                                            E, 0.1                                                                              0.12%  10    45.6 ± 12.0.sup.a                                                                  3      2-6                                            F, 0.25                                                                               0%   5    50.4 ± 4.0.sup.a                                                                    3    0.5-6                                            F, 0.25                                                                             0.12%  5    39.8 ± 6.0.sup.a                                                                    5      3-7                                            G, 0.25                                                                               0%   5     33.6 ± 10.6.sup.a                                                                  4      4-5                                            G, 0.25                                                                             0.12%  5    50.2 ± 7.1.sup.a                                                                    6      3-8                                            __________________________________________________________________________       Notes                                                                         The compounds designated A through G in the above table are as follows:        A: 7desacetyl-7(2,3-dihydroxypropionyl)forskolin                               B: forskolin, namely,                                                          7acetoxy-8,13-epoxy-1α,6β,9trihydroxylabd-14-en-11-one.             C: 7desacetyl-7(methylaminocarbonyl)forskolin                                  D: 7desacetyl-6(tetrahydrofurano-2-yl)forskolin                                E: 7desacetyl-6(2,3-dihydroxypropionyl)forskolin                               F: 7desacetyl-7 N(2,3-dihydroxypropyl)aminocarbonyl!forskolin                  G: 7desacetyl-7trimethylacetylhydroxylaminocarbonylforskolin                   .sup.a Significantly different from pretreatment reading as determined by      the paired Students ttest; P < 0.05.                                           .sup.b No significant reduction.                                         

A similar test was conducted using normal Dutch Belt rabbits. The results are summarized in Table 2.

                                      TABLE 2                                      __________________________________________________________________________                      Maximal %                                                                              Time of                                                                             Times post-                                                  N    reduction outflow                                                                      maximal                                                                             administration                                   Drug Phenylephrine                                                                         (no. of                                                                             pressure (ROP)                                                                         % ROP                                                                               of significant                                   conc.                                                                               concentration                                                                         subjects)                                                                           (mean ± S.E.M.)                                                                     (hour)                                                                              ROP (hour)                                       __________________________________________________________________________     A, 0.1%                                                                               0%   5    28.2 ± 7.5.sup.a                                                                    1    0.5-3                                            A, 0.5%                                                                               0%   14   17.5 ± 5.1.sup.a                                                                    1    0-1                                              A, 1.0%                                                                               0%   5    40.0 ± 7.4.sup.a                                                                    3    1.5-8                                            A, 0.1%                                                                             0.12%  5    26.8 ± 7.8.sup.a                                                                    9    7-9                                              A, 0.25%                                                                            0.12%  10   20.1 ± 4.8.sup.a                                                                    8    4-8                                              A, 0.5%                                                                             0.12%  5     61.0 ± 13.2.sup.a                                                                  6     2-24                                            A, 1.0%                                                                             0.12%  10    47.9 ± 10.3.sup.a                                                                  10    2-24                                            A, 2.0%                                                                             0.12%  5    54.6 ± 8.8.sup.a                                                                    6    3-8                                              C, 0.1%                                                                               0%   10   17.4 ± 4.5.sup.a                                                                    1.5  1-2                                              C, 0.25%                                                                              0%   5    21.4 ± 3.2.sup.a                                                                    3    2-4                                              C, 0.1%                                                                             0.12%  5    38.6 ± 8.0.sup.a                                                                    1.5  1-6                                              C, 0.25%                                                                            0.12%  5     46.6 ± 13.4.sup.a                                                                  1.5  1-6                                              C, 0.5%                                                                             0.12%  5    34.0 ± 5.1.sup.a                                                                    4    1-6                                              H, 0.25                                                                               0%   5    25.4 ± 7.0.sup.a                                                                    5    5-6                                              H, 0.25%                                                                            0.12%  5    38.0 ± 4.0.sup.a                                                                    4    3-7                                              I, 0.25%                                                                              0%   5    17.8 ± 3.0.sup.a                                                                    2    2-5                                              I, 0.25%                                                                            0.12%  5     48.0 ± 11.0.sup.a                                                                  7    3-7                                              __________________________________________________________________________       Notes                                                                         The compounds designated H and I in the above table are as follows:            H: 7desacetyl-7(2-hydroxyethylaminocarbonyl)forskolin                          I: 7desacetyl-7hydroxyaminocarbonylforskolin                                   .sup.a Significantly different from pretreatment reading as determined by      the paired Students ttests, P < 0.05.                                    

As a second aspect of this invention, the present inventors have found that when para-aminoclonidine (which is known to be an α₂ -adrenoreceptor agonist and has the chemical structure depicted as Formula II below) is combined with labdane compounds of Formula I in a suitable concentration, a rapid and substantial reduction in intraocular pressure is achieved with little or no hyperemia or irritation which may otherwise occur when such labdane compounds alone are used. Thus, para-aminoclonidine (PAC) potentiates the intraocular pressure lowering effect of the labdane compounds and also minimizes the extent of occurrence of hyperemia and irritation. In particular, PAC affords a rapid onset of reduction in intraocular pressure (IOP). ##STR10##

A preferred concentration range of para-aminoclonidine is between 0.003% and 0.1%, more preferably between 0.005% and 0.05%. When the PAC concentration is above 0.1 weight % in the ocular composition, a substantial mydriasis tends to occur, whereas when it is below 0.003%, the advantageous effects afforded by PAC tends not to be substantial. It is noteworthy that even at a low concentration of 0.01 weight %, PAC affords substantial advantageous effects. Typically, the concentration of the labdane compound in the ocular composition comprising PAC is between 0.1% and 1.0% by weight. Any suitable vehicle can be used for the ocular composition constituting the second aspect of this invention such as the one described earlier for the ocular composition comprising phenylephrine which constitutes the first aspect of this invention.

The method of administration of the second ocular composition of this invention is substantially the same as described earlier for the first ocular composition of this invention.

In ascertaining the effect of the second aspect of this invention, another set of experiments was conducted using another set of NZW rabbits in which the maximal percentage reduction in outflow pressure (ROP), time period of significant ROP and presence or absence of hyperemia, irritaiton, lacrimation and/or mydriasis were examined. For this purpose, 7β-desacetyl-7β-(methylaminocarbonyl)forskolin was used as a representative of the forskolin compounds of Formula I. The results are shown in Table 3 (The control data is different from the one presented in Table 1, because a new set of experiments using a new set of NZW rabbits was conducted).

                  TABLE 3                                                          ______________________________________                                                                   Times post                                                                     administration                                                       Maximal   of significant                                       Treatment.sup.a                                                                         (N)    % ROP.sup.b                                                                              ROP (Hr) Comments                                    ______________________________________                                         Compound C                                                                              15     .sup. 29.0 ± 3.6.sup.c                                                                1-4      moderate                                    (0.25%)                            hyperemia; and                                                                 lacrimation                                 Compound C                                                                              5      54.0 ± 7.9                                                                            1/2-4    miminal                                     (0.25%) plus                       hyperemia; no                               PAC (0.01%)                        mydriasis                                   Compound C                                                                              5      41.4 ± 2.5                                                                            1/2-4    minimal                                     (0.25%) plus                       hyperemia; no                               PAC (0.03%)                        mydriasis                                   Compound C                                                                              5      53.8 ± 9.4                                                                            1/2-5    no hyperemia                                (0.25%) plus                       or irritation;                              PAC (0.1%)                         maximal                                                                        mydriasis                                   ______________________________________                                           Notes                                                                         .sup.a : All ocular compositios applied topically to the eye                   .sup.b : Reduction in outflow pressure                                         .sup.c : Mean ± S.E.M.                                                      "N" signifies number of subjects.                                         

We claim:
 1. An intraocular pressure lowering composition for topical administration which comprises a pharmaceutically acceptable carrier and effective hyperemia suppressing and intraocular pressure lowering amounts of p-aminochlonidine and 7-β-desacetyl-7β-(methylaminocarbonyl)forskolin wherein the concentration of p-aminochlonidine in the composition is within the range of 0.003-0.1 weight percent and the concentration of the forskolin compound in the composition is in the range of about 0.25 weight percent.
 2. A method of lowering intraocular pressure without causing substantial redness in the eye of a mammal including human which comprises lowering the intraocular pressure of the eye by topical adminstration of the composition of claim
 1. 